A vaccine too far?

With no specific antiviral medications against dengue available and the control of mosquito populations, which spread the disease, proving difficult, an efficacious vaccine would be hugely beneficial.

Vaccines against yellow fever and Japanese encephalitis, caused by closely related viruses, are already available. Yet, coming up with one against dengue has been anything but straightforward.

One problem has been that the dengue virus takes four forms, known as serotypes. Those infected by a virus of one serotype develop lifelong immunity to that form but not the others. A dengue vaccine would therefore need to raise immunity against all four serotypes. Vaccines using a combination of viruses are already being used for measles, mumps and rubella as well as polio.

A major concern has been whether antibodies generated by a dengue vaccine could make people vulnerable to life-threatening forms of the disease. Epidemiological studies indicated that the vast majority of severe dengue cases occurred in those who had previously been infected by a virus of a different serotype. In such individuals, antibodies produced in the earlier infection were forming complexes with the later viruses, leading to an‘antibody-dependent enhancement of infection’ that worsened the disease.

But, on the other hand, only a small proportion of secondary dengue cases progressed to severe disease. Other factors, such as an individual’s genetic predisposition and nutritional status, could be important in that progression.

“Whatever the role of antibody-dependent enhancement, it seems that a vaccine inducing a long-lived neutralising antibody response against all four serotypes simultaneously should not induce any risk in this respect,” noted a review paper published in the medical journal Lancet Infectious Diseases.

A number of vaccines against dengue, using varying approaches, are being tested. The one developed by Sanofi Pasteur has progressed farthest in clinical trials. That vaccine is based on a weakened virus used in the yellow fever vaccine that had been engineered to carry genes for two dengue virus proteins.

A phase-2b clinical trial of the Sanofi Pasteur vaccine, which was carried out in Thailand, showed that it had a good safety profile, with no sign of the antibody-dependent enhancement that had been feared. But, sadly, it provided disappointingly poor protection.

The vaccine’s overall efficacy was only about 30 per cent. However, it gave good protection against three serotypes but failed to do so against the dominant serotype that produced most of the dengue cases during the trial. (For more details, see ‘Dengue still retains its deadly bite,’ The Hindu, September 11, 2012.)

The trial raised issues of whether immune mechanisms that can protect people against dengue are sufficiently well understood. A good vaccine could therefore be some way off.